The complement (C1) system is comprised of critical host innate immune mediators that help control invading organisms. Activation of C'is also a major link between the innate and adaptive immune systems and serves to augment both humoral and cellular immune responses. Orthopoxviruses encode secreted proteins that inhibit host C'-activation and block C'-mediated virus neutralization and inflammation. Thus, the poxvirus genes that encode complement control proteins (CCP) are ideal candidates with which to further attenuate smallpox vaccines. Importantly, it is not known whether manipulating these CCPs could also augment C'-enhanced adaptive immunity to the virus. We hypothesize that the vaccinia complement control protein (VCP) is a virulence factor with both a central role in protecting the virus from innate immunity and an immunoregulatory role that down regulates the magnitude, duration, and quality of antigen-specific T and B cell responses. We further hypothesize that by altering the VCP gene we can both further attenuate the virus to make a safer vaccine as well as enhance adaptive immune responses that would confer superior protection. To develop candidate smallpox vaccines that manipulate the function of VCP, we will: 1. Define the in vitro replication and in vivo pathogenicity of vaccinia virus mutants in which we selectively modify the VCP gene to manipulate its function. 2. Define the humoral and cellular immune responses to smallpox vaccines with modified VCP functions. 3. Define the protection conferred by vaccinations with viruses containing modified VCP in the context of both orthopoxvirus and heterologous challenge models. We believe that VCP is a promising target for novel vaccine strategies that has the potential to enhance both the safety and immunogenicity of next generation smallpox vaccines